During the past FYs, several labs independently validated neuroprotection by p5 peptide after systemic i.p. injections or after AAV-9 delivery in animal models of PD and AD, respectively. In addition, p5 was shown to reduce the infarct size in an ischemic stroke model. These results demonstrate peptide efficacy and safety at least during short term applications, but they don't address potential long-term safety issues. The safety and efficacy of long-term systemic use of the peptide or focal peptide expression is critically important before any clinical use should even be considered. Potential detrimental effects of p5 on normal, synaptic Cdk5/p25 activity, which plays a role in LTD and neuroplasticity, must be ruled out. Evidence suggests that there are two types of Cdk5/p25 activities in neurons: normal synaptic and hyperactive cytoplasmic. Recent evidence does suggest that p5 selectively can reduce aberrant cytoplasmic Cdk5/p25 hyperactivity without interfering with synaptic plasticity. LV vectors created by our proposed project could directly be used to generate transgenic mice that express the secreted and cell-penetrating version of the peptide in most cells. This is a very important step to verify safety. The development of healthy transgenic mice, which express this new p5 peptide in every cell, behave normally and show normal cognition and motor functions, would be strong evidence for the safety of the peptide. Transgenic mice are an elegant solution to address key safety issues, while allowing to verify therapeutic efficacy in various animal disease models. It is anticipated that these mice resist neurodegeneration and ameliorate associated immune responses. The p5 fragment of p35 is highly conserved in most lab animals and in humans and obtained results will be relevant across species. Before extensive efficacy tests with the peptide are started, it would be more cost-effective and less labor-intensive to first generate these transgenic p5 mice to verify safety. In FY19, no research funds were provided by the IRP and the main focus of the study focused on important literature searches trying to further refine the ideas and to verify the feasibility of our proposed research plans. These plans were compared to approaches by other labs in order to better understand their limitations and to evaluate their therapeutic potential in humans.